1. Field of the Invention
This invention relates to polynucleotides and vectors, to compositions containing the polynucleotides and vectors, to polypeptides and polypeptide compositions, and to their use.
2. Description of Related Art
CTL-mediated protection against tumors has been documented in mouse experimental models (1). In view of our refined comprehension of the molecular structures recognized by CTL, the search for human tumor-derived CTL epitopes has been undertaken in many laboratories, as best exemplified for melanomas (2). Subsequently, clinical trials using peptide-based immunization protocols provided encouraging results (3). However, the selection of peptide(s) and vaccine strategy remain difficult in view of the number of candidate peptides and variety of immunization strategies. An animal model allowing a controlled evaluation of the immunogenic potential of the epitopic peptides and of the immunization strategies would be of interest before human immunotherapeutic trials.
Classical H.A. class I transgenic mice (which still express their own H-2 class I Classical H.A. class I transgenic mice (which still express their own H-2 class I molecules) have been derived for such purposes (4). However, unless the third domain of the human molecules was substituted with the corresponding mouse domain, the peripheral CTL repertoire of these mice was inefficiently mobilized by the transgenic molecules due to poor interaction with mouse CD8 molecules (5). Accordingly, improved usage of H.A. class I molecules has been documented in transgenic strains expressing chimeric constructs (a1, a2 human, and a3 mouse) and exploited for the study of CTL responses against certain viral and tumor epitopic peptides (6, 7). Nevertheless, in such mice we observed a profound bias in favor of H-2 restricted CTL responses (H. Firat, unpublished observations). To circumvent that bias, we derived a strain of mice in which the H-2 Db and mouse b2-microglobulin (β2m) genes have been disrupted and which expresses a chimeric (a1, a2 human, and a3 mouse) HLA-A2.1 heavy chain covalently linked to human b2m light chain. We named this chimeric molecule the HHD molecule. In HHD transgenic mice, the transgenic molecules are the only class I molecules serologically detectable on cell surfaces and are used efficiently by CTL in responses against viruses (8). We report here the use of these mice to compare the immunogenic potential of H.A.-A2.1-restricted human tumor-associated CTL epitopes and different strategies of immunization.